In this study, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 mo) and old (30 mo) rats. Using 2-D DIGE, we have obtained 2-D gel maps of 301 identified non-redundant proteins from rat aorta and observed 18 proteins that significantly change abundance with aging. Utilizing iTRAQ, 921 proteins were quantified and between both methods, 50 proteins were shown to have significantly different age-associated abundance. Notably, proteomic analysis shows that one protein of interest, MFG-E8, significantly increases in abundance in old rat aorta. Transcription and translation analysis demonstrated that aortic MFG-E8 mRNA and protein levels increase with aging in several mammalian species, including humans. Dual immunolabeling shows that MFG-E8 colocalizes with both angiotensin II (Ang II) and monocyte chemoattractant protein-1 (MCP-1) within vascular smooth muscle cells (VSMC) of the thickened aged aortic wall. Exposure of early passage VMSC from young aorta to Ang II markedly increases MFG-E8 and enhances invasive capacity to levels observed in VSMC from old rats. Treatment of VSMC with MFG-E8 increases MCP-1 and VSMC invasion that are inhibited by the MCP-1 receptor blocker, vCCI. Silencing MFG-E8 RNA substantially reduces MFG-E8 expression and VSMC invasion capacity. Thus, arterial MFG-E8 significantly increases with aging and is a pivotal relay element within the Ang II MCP-1/VSMC invasion signaling cascade. Importantly, we have identified that aging arterial MFG-E8-enriched VSMC are activated and proliferating both in vivo and in vitro. Increased MFG-E8 in VSMC triggers phosphorylation of ERK1/2, augments levels of PCNA and CDK4, increases BrdU incorporation and promotes growth. The knockdown of MFG-E8 reduces rate of cell cycling, accelerating signaling molecules PCNA and CDK4 expression, facilitating cell entry into a growth-arrested state. Furthermore, we find that av5 and PDGF are upregulated with MFG-E8 and also are elements to relay proliferative signals to aging VSMC. In addition, the profibrogenic signaling molecules TGF-&#946;1, T&#946;RII, p-SMAD 2/3, and collagen are up-regulated in both MFG-E8 treatment and Vasorin silencing of young VSMCs, up to the levels in old cells. Conversely, expression of these profibrogenic molecules is down-regulated in MFG-E8 null and silenced old VSMCs, reaching the levels of young cells. Impressively, exposure of VSMCs to exogenous MFG-E8 increases the profibrotic levels of TGF-&#946;1, T&#946;RII, p-SMAD 2/3, and collagen in the old VSMCs. Further, young VSMCs resistance to MFG-E8 profibrogic responses is abolished by up-regulation of cav-1 signaling. Taken together, the present findings, for the first time, suggest that the imbalance of MFG-E8 and Cav-1 signaling in the lipid raft is a key molecular event to collagen production of VSMCs with advancing age.